Induction of proinflammatory
cytokines IL-6 and
TGF-beta1 are the hallmark of human
pancreatitis.
Cerulein pancreatitis is similar to human edematous
pancreatitis involving dysregulation of digestive
enzyme production, cytoplasmic vacuolization, and increased
cytokine production. We previously showed that
cerulein induced IL-1beta expression through the
Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway in pancreatic acinar cells. Suppressor of
cytokine signaling (SOCS) is a negative feedback regulator of JAK/STAT signaling. In this study, we demonstrate that SOCS 3 is induced by
cerulein in pancreatic acinar AR42J cells and in the rat pancreas. In both AR42J cells and rat pancreas,
cerulein induced expression of
IL-6 and
TGF-beta1, which is enhanced by transfection or injection of SOCS 3
antisense oligonucleotide (AS ODN). Pre-treating
cerulein-stimulated AR42J cells or rats with the
peroxisome proliferator activated receptor-gamma (
PPAR-gamma)
ligands,
15d-PGJ2 and
troglitazone, induced SOCS 3 expression and inhibited JAK2/STAT3 activation. This treatment regimen also inhibited
IL-6 and
TGF-beta1 induction, vacuolization, and alpha-smooth muscle actin (alpha-SMA) expression. Thus, SOCS 3 expression is associated with a reduction in
IL-6 and
TGF-beta1 expression,
edema formation, vacuolization, and alpha-SMA expression, possibly by direct regulation of JAK2/STAT3 signaling.
15d-PGJ2 and
troglitazone are potentially useful
pancreatitis therapies by suppressing the JAK2/STAT3 inflammatory signaling through SOCS 3 induction.